Multifunctional Neuroprotective Drugs for the Treatment of Alzheimer's Disease

  • Cornelis J. Van der Schyf
  • Werner J. Geldenhuys
  • Moussa B. H. Youdim

The concept of targeting multiple disease etiologies that lead to cognitive impairment in the neurodegenerative disorder Alzheimer’s disease (AD) is challenging the widely held assumption that “ silver bullet” agents are superior to “ dirty drugs” in drug therapy. Accumulating evidence in the literature suggests that a drug with two or more mechanisms of action targeted at multiple etiologies of the same disease may offer more therapeutic benefit in certain disorders than a drug that targets one disease etiology only. In addition, such multiple mechanism/multifunctional drugs may exhibit a more favorable side effect profile than a polypharmaceutical combination of several drugs that individually target the same disease etiologies than those identified for a single multifunctional drug. In this chapter, we offer a synopsis of therapeutic strategies and novel investigative drugs, developed in our own and other laboratories, which modulate multiple disease targets associated with AD and cognitive impairment disorders.


NMDA Receptor Dementia With Lewy Body Nicotinic Acetylcholine Receptor NMDA Receptor Antagonist Adenosine Receptor Antagonist 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akk, G., & Steinbach, J. H. (2005). Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. Journal of. Neuroscience, 25, 1992–2001.CrossRefPubMedGoogle Scholar
  2. Arundine, M., & Tymianski, M. (2004). Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cellular and Molecular Life Sciences, 61, 657–668.CrossRefPubMedGoogle Scholar
  3. Avramovich, Y., Amit, T., & Youdim, M. B. H. (2002). Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. Journal of Biological Chemistry, 277, 31466–31473.CrossRefPubMedGoogle Scholar
  4. Avramovich-Tirosh, Y., Reznichenko, L., Amit, T., Zheng, H., Fridkin, M., Weinreb, O., et al. (2006). Neurorescue Activity, APP Regulation and Amyloid-β Peptide Reduction by Novel Multi-Functional Brain Permeable Iron- Chelator- Antioxidants, M-30 and Green Tea Polyphenol, EGCG. Current Alzheimers Disease Research (in press).Google Scholar
  5. Ben Shachar, D., Kahana, N., Kampel, V., Warshawsky, A., & Youdim, M. B. H. (2004). Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology, 46, 254–263.CrossRefGoogle Scholar
  6. Breitner, J. C., Welsh, K. A., Helms, M. J., Gaskell, P. C., Gau, B. A., Roses, A. D., et al. (1995). Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiology of Aging, 16, 523–530.CrossRefPubMedGoogle Scholar
  7. Buxbaum, J. D., Cullen, E. I., & Friedhoff, L. T. (2002). Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Frontiers in Bioscience, 1, 50–59.CrossRefGoogle Scholar
  8. Castagnoli, N, Jr., Petzer, J. P., Steyn, S., Castagnoli, K., Chen, J. F., Schwarzschild, M. A., et al. (2003). Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists. Neurology, 61, (11 Suppl. 6), S62–S68.PubMedGoogle Scholar
  9. Chen, J. F., Steyn, S., Staal, R., Petzer, J. P., Xu, K., Van Der Schyf, C. J., et al. (2002). 8-(3-Chlorostyryl) caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. Journal of Biological Chemistry, 277, 36040–36044.CrossRefPubMedGoogle Scholar
  10. Christiaans, J. A. M., & Timmerman, H. (1996). Cardiovascular hybrid drugs: Combination of more than one pharmacological property in one single molecule. European Journal of Pharmaceutical Sciences, 4, 1–22.CrossRefGoogle Scholar
  11. Chung, K. F., & Adcock, I. M. (2004). Combination therapy of long-acting beta2-adrenoceptor agonists and corticosteroids for asthma. Treatments in Respiratory Medicine, 3, 279–289.CrossRefPubMedGoogle Scholar
  12. Collins, F., & Lile, J. D. (1989). The role of dihydropyridine-sensitive voltage-gated calcium channels in potassium-mediated neuronal survival. Brain Research, 502, 99–108.CrossRefPubMedGoogle Scholar
  13. Cordle, A., & Landreth, G. (2005). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. Journal of Neuroscience, 25, 299–307.CrossRefPubMedGoogle Scholar
  14. Dajas-Bailador, F. A., Heimala, K., & Wonnacott, S. (2003). The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Molecular Pharmacology, 64, 1217–1226.CrossRefPubMedGoogle Scholar
  15. Dall'Igna, O. P., Porciuncula, L. O., Souza, D. O., Cunha, R. A., & Lara, D. R. (2003). Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. British Journal of Pharmacology, 138, 1207–1209.CrossRefPubMedGoogle Scholar
  16. Dall'Igna, O. P., Souza, D. O., & Lara, D. R. (2004). Caffeine as a neuroprotective adenosine receptor antagonist. Annals of Pharmacotherapy, 38, 717–718.CrossRefPubMedGoogle Scholar
  17. Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., et al. (2003). RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature Medicine, 9, 907–913.CrossRefPubMedGoogle Scholar
  18. Dengiz, A. N., & Kershaw, P. (2004). The clinical efficacy and safety of galantamine in the treatment of Alzheimer's disease. CNS Spectrums. 9, 377–392.PubMedGoogle Scholar
  19. Farlow, M. R. (2004). NMDA receptor antagonists. A new therapeutic approach for Alzheimer's disease. Geriatrics, 59, 22–27.PubMedGoogle Scholar
  20. Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., et al. (2001). Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proceedings of the National Academy of Sciences U S A, 98, 5856–5861.CrossRefGoogle Scholar
  21. Floden, A. M., Li, S., & Combs, C. K. (2005). Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. Journal of Neuroscence, 25, 2566–2575.CrossRefGoogle Scholar
  22. Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999). The cholinergic hypothesis of Alzheimer's disease: a review of progress. Journal of Neurology, Neurosurgery, and Psychiatry, 66, 137–147.CrossRefPubMedGoogle Scholar
  23. Friedhoff, L. T., Cullen, E. I., Geoghagen, N. S., & Buxbaum, J. D. (2001). Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. International Journal of Neuropsychopharmacology, 4, 127–130.PubMedGoogle Scholar
  24. Gal, S., Zheng, H., Fridkin, M., & Youdim, M. B. H. (2005). Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases, II; in vivo selective brain monoamine oxidase inhibition and prevention of MPTP induced striatal dopamine depletion. Journal of Neurochemistry, 95, 79–88.CrossRefPubMedGoogle Scholar
  25. Geldenhuys, W. J., Malan, S. F., Bloomquist, J. R., Marchand, A. P., & Van der Schyf, C. J. (2005). Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives. Medical Research Reviews, 25, 21–48.CrossRefGoogle Scholar
  26. Geldenhuys, W. J., Malan, S. F., Bloomquist, J. R., and Van der Schyf, C. J. (2007). Structure-activity relationships of pentacycloundecylamines at the N-methly-D-aspartate receptor. Bioorg. Med. Chem, 15, 1525–1532.CrossRefPubMedGoogle Scholar
  27. Gerriets, T., Stolz, E., Walberer, M., Kaps, M., Bachmann, G., & Fisher, M. (2003). Neuroprotective effects of MK-801 in different rat stroke models for permanent middle cerebral artery occlusion: adverse effects of hypothalamic damage and strategies for its avoidance. Stroke, 34, 2234–2239.CrossRefPubMedGoogle Scholar
  28. Goruglu, A., Kins, T., Cobanoglu, S., Unal, F., Izgi, N. I., Yanik, B., et al. (2000). Reduction of edema and infarction by Memantine and MK-801 after focal cerebral ischaemia and reperfusion in rat. Acta Neurochirurgica (Wien), 142, 1287–1292.CrossRefGoogle Scholar
  29. Green, R. A., Odergren, T., & Ashwood, T. (2003). Animal models of stroke: do they have value for discovering neuroprotective agents? Trends in Pharmacological. Sciences, 24, 402–408.CrossRefGoogle Scholar
  30. Greenblatt, H. M., Kryger, G., Lewis, T., Silman, I., & Sussman, J. L. (1999). Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 Å resolution. FEBS Letters. 463, 321–326.CrossRefPubMedGoogle Scholar
  31. Gurwitz, J. H. (2004). Polypharmacy: a new paradigm for quality drug therapy in the elderly? Archives of Internal Medicine, 164, 1957–1959.CrossRefPubMedGoogle Scholar
  32. Hernandez-Pineda, R., Chow, A., Amarillo, Y., Moreno, H., Saganich, M., Vega-Saenz de Miera, E. C., et al. (1999). Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K+ current in projecting neurons from the globus pallidus. Journal of Neurophysiology, 82, 1512–1528.PubMedGoogle Scholar
  33. Horn, J., de Haan, R. J., Vermeulen, M., Luiten, P. G., & Limburg, M. (2001). Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke, 32, 2433–2438.CrossRefPubMedGoogle Scholar
  34. Hynd, M. R., Scott, H. L., & Dodd, P. R. (2004). Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochemistry International, 45, 583–595.CrossRefPubMedGoogle Scholar
  35. Jain, K. K. (2000). Evaluation of memantine for neuroprotection in dementia. Expert Opinion in Investigational Drugs, 9, 1397–1406.CrossRefGoogle Scholar
  36. Kadaba, P. K. (2003). Rational drug design and the discovery of the delta2–1, 2, 3-triazolines, a unique class of anticonvulsant and antiischemic agents. Current Medicinal Chemistry, 10, 2081–2108.CrossRefPubMedGoogle Scholar
  37. Keith, C. T., Borisy, A. A., & Stockwell, B. R. (2005). Multicomponent therapeutics for networked systems. Nature Reviews Drug Discovery, 4, 71–78.CrossRefPubMedGoogle Scholar
  38. Kemp, J. A., & McKernan, R. M. (2002). NMDA receptor pathways as drug targets. Nature Neuroscience, 5(Suppl.), 1039–1042.CrossRefPubMedGoogle Scholar
  39. Kiewert, C., Hartmann, J., Stoll, J., Thekkumkaa, T. J., Van der Schyt, C. J., Klein, J. NGP1–01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated clacium channels, Neurochem Res. 2006, 31, 503–508.CrossRefGoogle Scholar
  40. Lipton, P. (1999). Ischemic cell death in brain neurons. Physiological Reviews, 79, 1431–1568.PubMedGoogle Scholar
  41. Maia, L., & de Mendonca, A. (2002). Does caffeine intake protect from Alzheimer's disease? European Journal of Neurology, 9, 377–382.CrossRefPubMedGoogle Scholar
  42. Malan, S. F., Dyason, K., Wagenaar, B., Van Der Walt, J. J., & Van Der Schyf, C. J. (2003) The structure and ion channel activity of 6-benzylamino-3-hydroxyhexa- cyclo [, 7.04, 12.05, 10.09, 13]tridecane. Archiv der Pharmazie, 336, 127–133.CrossRefPubMedGoogle Scholar
  43. Malan, S. F., Van der Walt, J. J., & Van der Schyf C. J. (2000). Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity. Archiv der Pharmazie, 333, 10–16.CrossRefPubMedGoogle Scholar
  44. Marco, J. L., de los Rios, C., Garcia, A. G., Villarroya, M., Carreiras, M. C., Martins, C., et al. (2004). Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase/butyrylcholinesterase and modulators of Ca2+ channels and nicotinic receptors. Bioorganic and Medicinal Chemistry, 12, 2199–2218.CrossRefPubMedGoogle Scholar
  45. Menge, T., Hartung, H. P., & Stuve, O. (2005). Opinion: Statins - a cure-all for the brain? Nature Reviews Neuroscience, 6, 325–331.CrossRefPubMedGoogle Scholar
  46. Moriguchi, S., Marszalec, W., Zhao, X., Yeh, J. Z., & Narahashi, T. (2003). Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons. Journal of Pharmacology and Experimental Therapeutics, 307, 160–167.CrossRefPubMedGoogle Scholar
  47. Moriguchi, S., Marszalec, W., Zhao, X., Yeh, J. Z., & Narahashi, T. (2004). Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. Journal of Pharmacology and Experimental Therapeutics, 310, 933–942.CrossRefPubMedGoogle Scholar
  48. Morphy, R., Kay, C., & Rankovic, Z. (2004). From magic bullets to designed multiple ligands. Drug Discovery Today, 9, 641–651.CrossRefPubMedGoogle Scholar
  49. Nan, F., Bzdega, T., Pshenichkin, S., Wroblewski, J. T., Wroblewska, B., Neale, J. H., et al. (2000). Dual function glutamate-related ligands: discovery of a novel, potent inhibitor of glutamate carboxypeptidase II possessing mGluR3 agonist activity. Journal of Medicinal Chemistry, 43, 772–777.CrossRefPubMedGoogle Scholar
  50. Narahashi, T., Moriguchi, S., Zhao, X., Marszalec, W., & Yeh, J. Z. (2004). Mechanisms of action of cognitive enhancers on neuroreceptors. Biological and Pharmaceutical Bulletin, 27, 1701–1706.CrossRefPubMedGoogle Scholar
  51. Nicoletti, F., Bruno, V., Copani, A., Casabona, G., & Knopfel, T. (1996). Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders? Trends in Neurosciences, 19, 267–271.CrossRefPubMedGoogle Scholar
  52. Nishizaki, T., Matsuoka, T., Nomura, T., Sumikawa, K., Shiotani, T., Watabe, S., et al. (1998). Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways. Molecular Pharmacology, 53, 1–5.PubMedGoogle Scholar
  53. O'Neill, M. J., Bath, C. P., Dell, C. P., Hicks, C. A., Gilmore, J., Ambler, S. J., et al. (1997). Effects of Ca2+ and Na + channel inhibitors in vitro and in global cerebral ischaemia in vivo. European Journal of Pharmacology, 332, 121–131.CrossRefPubMedGoogle Scholar
  54. Orozco, C., de Los Rios, C., Arias, E., Leon, R., Garcia, A. G., Marco, J. L., et al. (2004), ITH4012 (ethyl 5-amino-6, 7, 8, 9-tetrahydro-2-methyl-4-phenylbenzol[1, 8] naphthyridine-3-carboxylate), a novel acetylcholinesterase inhibitor with “calcium promotor” and neuroprotective properties. Journal of Pharmacology and Experimental Therapeutics, 310, 987–994.CrossRefPubMedGoogle Scholar
  55. Ovbiagele, B., Kidwell, C. S., Starkman, S., & Saver, J. L. (2003). Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Current Treatment Options in Cardiovascular Medicine, 5, 441–449.CrossRefPubMedGoogle Scholar
  56. Oyaizu, M., & Narahashi, T. (1999). Modulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetam. Brain Research, 822, 72–79.CrossRefPubMedGoogle Scholar
  57. Pahan, K., Sheikh, F. G., Namboodiri, A. M., & Singh, I. (1997). Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. Journal of Clinical Investigation, 100, 2671–2679.CrossRefPubMedGoogle Scholar
  58. Parsons, C. G., Danysz, W., & Quack, G. (1999). Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data. Neuropharmacology, 38, 735–767.CrossRefPubMedGoogle Scholar
  59. Petzer, J. P., Steyn, S., Castagnoli, K. P., Chen, J. F., Schwarzschild, M. A., Van der Schyf, C. J., et al. (2003). Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists. Bioorganic and Medicinal Chemistry, 11, 1299–1310.CrossRefPubMedGoogle Scholar
  60. Prediger, R. D., Batista, L. C., & Takahashi, R. N. (2005). Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiology of Aging, 26, 957–964.CrossRefPubMedGoogle Scholar
  61. Rami, A., & Krieglstein, J. (1994). Neuronal protective effects of calcium antagonists in cerebral ischemia. Life Sciences, 55, 2105–2113.CrossRefPubMedGoogle Scholar
  62. Reisberg, B., Doody, R., Stoffler, A., Schmitt, F., Ferris, S., & Mobius, H. J. (2003). Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. New England Journal of Medicine, 348, 1333–13341.CrossRefPubMedGoogle Scholar
  63. Rich, J. B., Rasmusson, D. X., Folstein, M. F., Carson, K. A., Kawas, C., & Brandt, J. (1995). Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology, 45, 51–55.PubMedGoogle Scholar
  64. Riederer, P., Danielczyk, W., & Grunblatt, E. (2004). Monoamine oxidase-B inhibition in Alzheimer's disease. Neurotoxicology, 25, 271–277.CrossRefPubMedGoogle Scholar
  65. Rogers, J., Kirby, L. C., Hempelman, S. R., Berry, D. L., McGeer, P. L., Kaszniak, A. W., et al. (1993). Clinical trial of indomethacin in Alzheimer's disease. Neurology, 43, 1609–1611.PubMedGoogle Scholar
  66. Roth, B. L., Sheffler, D. J., & Kroeze, W. K. (2004). Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery, 3, 353–359.CrossRefPubMedGoogle Scholar
  67. Rutherford, G. W., Sangani, P. R., & Kennedy, G. E. (2003). Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection. Cochrane Database System Review, 4, CD002037.Google Scholar
  68. Sagi, Y., Weinstock, M., & Youdim, M. B. H. (2003). Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. Journal of Neurochemistry, 86, 290–297.CrossRefPubMedGoogle Scholar
  69. Sasaki, T., Eguchi, S., & Kiriyama, T. (1971). A facile synthesis of mono-oxa and aza-cage compounds via transanullar cyclizations. Tetrahedron Letters, 2651–2654.Google Scholar
  70. Sasaki, T, Kiriyama, E. T., & Hiroaki, O. (1974). Studies on hetero-cage compounds–VI transannular cyclizations in pentacyclo[, 7.04, 10.05, 9]undecan-3, 6-dione system. Tetrahedron, 30, 2707–2712.CrossRefGoogle Scholar
  71. Saura, J., Richards, J. G., & Mahy, N. (1994). Differential age-related changes of MAO-A and MAO-B in mouse brain and peripheral organs. Neurobiology of Aging, 15, 399–408.CrossRefPubMedGoogle Scholar
  72. Schmitt, B., Bernhardt, T., Moeller, H. J., Heuser, I., & Frolich, L. (2004). Combination therapy in Alzheimer's disease: a review of current evidence. CNS Drugs, 18, 827–844.CrossRefPubMedGoogle Scholar
  73. Sramek, J. J., & Cutler, N. R. (1999). Recent developments in the drug treatment of Alzheimer's disease. Drugs and Aging, 14, 359–373.CrossRefPubMedGoogle Scholar
  74. Van der Schyf, C. J., Squier, G. J., & Coetzee, W. A. (1986). Characterization of NGP 1–01, an aromatic polycyclic amine, as a calcium antagonist. Pharmacological Research Communications, 18, 407–417.CrossRefPubMedGoogle Scholar
  75. Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., et al. (2001). A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414, 212–216.CrossRefPubMedGoogle Scholar
  76. Wenk, G. L., Rosi, S., McGann, K., Hauss-Wegrzyniak, B. (2002). A nitric oxide-donating flurbiprofen derivative reduces neuroinflammation without interacting with galantamine in the rat. European Journal of Pharmacology, 453, 319–324.CrossRefPubMedGoogle Scholar
  77. Wilkinson, D., & Murray, J. (2001). Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease. International Journal of Geriatric Psychiatry, 16, 852–857.CrossRefPubMedGoogle Scholar
  78. Youdim, M. B. H. (2006). The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and M30. Current Alzheimer's Disease Research, 3, 541–550.CrossRefGoogle Scholar
  79. Youdim, M. B. H., Bar Am, O., Yogev-Falach, M., Weinreb, O., Maruyama, W., Naoi, M., et al. (2005). Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. Journal of Neuroscience Research, 79, 172–179.CrossRefPubMedGoogle Scholar
  80. Youdim, M. B. H., & Buccafusco, J. J. (2005a). CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases. Journal of Neural Transmission, 112, 519–537.CrossRefPubMedGoogle Scholar
  81. Youdim, M. B. H., & Buccafusco, J. J. (2005b). Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends in Pharmacological Sciences, 26, 27–35.CrossRefPubMedGoogle Scholar
  82. Youdim, M. B. H., Fridkin, M., & Zheng, H. (2005). Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mechanisms of Ageing and Development, 126, 317–326.CrossRefPubMedGoogle Scholar
  83. Zerkak, D., & Dougados, M. (2004). Benefit/risk of combination therapies. Clinical and Experimental Rheumatology, 5(Suppl. 35), S71–S76.Google Scholar
  84. Zhao, X., Yeh, J. Z., & Narahashi, T. (2001). Post-stroke dementia. Nootropic drug modulation of neuronal nicotinic acetylcholine receptors. Annals of the New York Academy of Sciences, 939, 179–186.PubMedCrossRefGoogle Scholar
  85. Zheng, H., Gal, S., Weiner, L. M., Bar-Am, O., Warshawsky, A., Fridkin, M., et al. (2005). Novel multifunctional neuroprotective iron chelator-monoamine oxidase drugs for neurodegenerative diseases; I. in vitro studies on iron chelation, antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. Journal of Neurochemistry, 95, 68–78.CrossRefPubMedGoogle Scholar
  86. Zheng, H., Weiner, L. M., Bar-Am, O., Epsztejn, S., Cabantchik, Z. I., Warshawsky, A., et al. (2005). Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorganic and Medicinal Chemistry, 13, 773–783.CrossRefPubMedGoogle Scholar
  87. Zheng H., Youdim, M. B. H., Weiner, L. M., & Fridkin, M. (2005a). Novel potential neuroprotective agents with both iron chelating and amino acid-based derivatives targeting central nervous system neurons. Biochemical Pharmacology, 70, 1642–1652.CrossRefPubMedGoogle Scholar
  88. Zheng, H., Youdim, M. B. H., Weiner, L. M., & Fridkin, M. (2005b). Synthesis and evaluation of peptidic metal chelators for neuroprotection in neurodegenerative diseases. Journal of Peptide Research, 66, 190–203.CrossRefPubMedGoogle Scholar
  89. Zlokovic, B. V. (2005). Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends in Neurosciences, 28, 202–208.CrossRefPubMedGoogle Scholar
  90. Zou, J. Y., & Crews, F. T. (2005). TNFalpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Research, 1034, 11–24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Cornelis J. Van der Schyf
    • 1
  • Werner J. Geldenhuys
    • 1
  • Moussa B. H. Youdim
    • 2
  1. 1.Department of Pharmaceutical SciencesNortheastern Ohio Universities College of PharmacyRootstownUSA
  2. 2.Technion-Rappaport Family-Faculty of Medicine Eve TopfU.S. National Parkinson Foundation Centers of Excellence for Neurodegenerative DiseasesIsrael

Personalised recommendations